title: Polymorphism in the TOMM40 gene modifies the risk of developing sporadic inclusion body myositis and the age of onset of symptoms.
abstract: A polyT repeat in an intronic polymorphism (rs10524523) in the TOMM40 gene, which encodes an outer mitochondrial membrane translocase involved in the transport of amyloid-β and other proteins into mitochondria, has been implicated in Alzheimer's disease and APOE-TOMM40 genotypes have been shown to modify disease risk and age at onset of symptoms. Because of the similarities between Alzheimer's disease and sporadic inclusion body myositis (s-IBM), and the importance of amyloid-β and mitochondrial changes in s-IBM, we investigated whether variation in poly-T repeat lengths in rs10524523 also influence susceptibility and age at onset in a cohort of 90 Caucasian s-IBM patients (55 males; age 69.1 ± 9.6). In carriers of APOE ε3/ε3 or ε3/ε4, genotypes with a very long (VL) poly-T repeat were under-represented in s-IBM compared to controls and were associated with a later age at symptom onset, suggesting that these genotypes may be protective. Our study is the first to suggest that polymorphisms in genes controlling mitochondrial function can influence susceptibility to s-IBM and have disease modifying effects. However, further studies in other s-IBM populations are needed to confirm these findings, as well as expression studies of different TOMM40 alleles in muscle tissue.
authors.affiliation: Australian Neuro-Muscular Research Institute, Centre for Neuromuscular and Neurological Disorders, The University of Western Australia, Queen Elizabeth II Medical Centre, Perth, Western Australia, Australia; Institute for Immunology & Infectious Diseases, Murdoch University, Western Australia, Australia. Electronic address: francis.mastaglia@anri.uwa.edu.au.
authors.forename: F L
authors.initials: FL
authors.lastname: Mastaglia
authors.forename: A
authors.initials: A
authors.lastname: Rojana-udomsart
authors.forename: I
authors.initials: I
authors.lastname: James
authors.forename: M
authors.initials: M
authors.lastname: Needham
authors.forename: T J
authors.initials: TJ
authors.lastname: Day
authors.forename: L
authors.initials: L
authors.lastname: Kiers
authors.forename: J A
authors.initials: JA
authors.lastname: Corbett
authors.forename: A M
authors.initials: AM
authors.lastname: Saunders
authors.forename: M W
authors.initials: MW
authors.lastname: Lutz
authors.forename: A D
authors.initials: AD
authors.lastname: Roses
mesh_terms: D017668:Age of Onset; D000368:Aged; D001057:Apolipoproteins E / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics*; D008875:Middle Aged; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D018979:Myositis, Inclusion Body / Q000235:genetics* / Q000401:mortality; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D019680:Trinucleotide Repeat Expansion / Q000235:genetics
chemical_list: D001057:Apolipoproteins E; D026901:Membrane Transport Proteins; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; C400783:TOMM40 protein, human
keywords: APOE; Age of onset; Sporadic IBM; Susceptibility; TOMM40